Malaria remains a significant threat to human health, with about 400 million people infected worldwide and about 2 million deaths per year, primarily children from tropical Africa. The effectiveness of malaria control programs has been significantly reduced due to the emergence of multiple-pesticide resistant mosquito populations and the worldwide spread of chloroquine resistance in Plasmodium falciparum. In addition, efforts toward vaccine development have shown little promise in providing a solution to this disease problem in the near future. The long- term objectives of the proposed research are to identify, isolate and characterize genes associated with the susceptibility and/or refractoriness of mosquito species to Plasmodium parasites, and to use this information to develop novel malaria disease control strategies aimed toward disrupting the parasite life cycle. The objectives of this project are based on the general hypothesis that genes associated with Plasmodium refractoriness can be identified and isolated using positional cloning techniques. The characterization of these genes will enhance malaria disease control efforts by 1) identifying novel agents through determining specific gene involvement in biochemical pathways or 2) identifying suitable candidate genes for the production of genetically engineered, refractory mosquito strains. The research examines the mosquito Aedes aegypti and its genetic relationship with the malarial parasite Plasmodium gallinaceum as a model system for elucidating genetic control mechanisms, because of the wealth of genetic information available for this mosquito and the close phylogenetic relationship of this parasite and the major human malarial parasite P. falciparum. The specific aims of the project are: (1) Fine-scale map genome regions identified as containing genes that influence Plasmodium vector competence, and (2) Isolate and identify genes contained within the redefined QTL regions.